An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models.
BACKGROUND
The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A 2A adenosine receptor (AR) agonist treated and untreated animals during experimental sepsis.


METHODS
Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (Escherichia coli or Staphylococcus aureus) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A 2A AR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days.


RESULTS
There was a significant survival benefit in mice infected with live E. coli (100% vs. 20%, p = 0.013) or S. aureus (60% vs. 20%, p = 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, p = 0.005). The serum concentrations of TNF-alpha, MIP-1 alpha, MCP-1, IFN-gamma, and IL-17 were decreased by ATL313 after LPS injection (p < 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (p < 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (p < 0.01).


CONCLUSIONS
Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.
Moore
Christopher C
CC
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Box 801342, Charlottesville, VA 22908, USA. ccm5u@virginia.edu
Martin
Edward N
EN
Lee
Grace H
GH
Obrig
Tom
T
Linden
Joel
J
Scheld
W Michael
WM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000188:drug therapy; D005260:Female; D007249:Inflammation / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D018805:Sepsis / Q000188:drug therapy*; D013203:Staphylococcal Infections / Q000188:drug therapy; D016019:Survival Analysis
C510376:ATL 313; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D010880:Piperidines; D043705:Receptor, Adenosine A2A; D002443:Ceftriaxone